Almost nothing is known about how neurons migrate, or about the molecular mechanism regulating this migration. Understanding these mechanisms is critical for our understanding of childhood epilepsy and mental retardation, as defects in neuronal migration frequently underlie these disorders. Additionally, one of the major hurdles in neuronal transplantation or regeneration following damage is poor neuronal migration into target areas, which may be overcome through approaches derived from a better understanding of how neurons migrate. One common inherited cause of severe mental retardation and epilepsy in humans is classical lissencephaly, defined by a lack of cortical gyri and sulci formation and due to a failure of neurons to properly migrate. Mutations in either of two genes, doublecortin (DCX) or lissencephalyI (LIS1), leads to severe generalized defects in neuronal migration and produces nearly identical lissencephaly in humans. A mutation in the cdk5 gene in mouse also leads to a defect in neuronal migration that is strikingly similar to human lissencephaly. The central hypothesis of this application is that these common mutant phenotypes suggest that there may be interactions between the encoded proteins. The predicted DCX and LIS1 proteins are entirely novel, suggesting they may help define novel molecular mechanisms of neuronal migration, and both were previously shown to function as microtubuleassociated proteins that are localized around the nucleus. The cdk5 gene is a serinethreonine kinase that phosphorylates some cytoskeletal proteins. However, the role of DCX, LIS1 and cdk5 in neuronal migration is unknown. Additionally, despite the very similar mutant phenotypes, it is untested whether these proteins interact directly to mediate their effect or even act in a common pathway. Therefore the Specific Aims of this proposal are to determine whether: 1) There are genetic or physical interactions between DCX and LIS1. 2) DCX and LIS1 function to regulate nuclear movement during neuronal migration. 3) DCX is regulated by cdk5 during neuronal migration.